Phenyl benzoic acid compounds in compositions and methods for treating inflammation

ABSTRACT

The invention relates to a method of treating inflammation by administering substituted 5-(phenyl) benzoic acids, esters and non-toxic pharmaceutically accepted salts thereof to patients.

United States Patent Ruyle et al.

[ July 4, 1972 I54] PIIENYL BENZOIC ACIDCOMPOUNDS IN COMPOSITIONS ANDMETHODS FOR TREATING INFLAMMATION [72] Inventors: William V. Ruyle,Scotch Plains; Lewis H. Sarett, Skillman; Alexander R. Matzuk,

Colonia, all of NJ.

[73] Assignee: Merck & Co. Inc., Rahway, NJ.

[22] Filed: June 9, 1970 [21] Appl. No.: 44,868

Related US. Application Data 52 U.S.Cl ..424/230,424/308,424/3ll,

' 424 315, 424/317, 424/324 51 lnt.Cl ..A61v27/00 5s FieldofSearch ..424317,230,311

[56] References Cited UNITED STATES PATENTS 2,744,916 5/1956 Sahyumetal. ..424/3l7 Primary Examiner-Stanley J. Friedman Attorney Michael C.Sudol, Jr., H. E. Westlake, Jr. and l. Louis Wolk [57] ABSTRACT Theinvention relates to a method of treating inflammation by administeringsubstituted S-(phenyl) benzoic acids, esters and non-toxicpharmaceutically accepted salts thereof to patients.

22 Claims, No Drawings PHENYL BENZOIC ACID COMPOUNDS IN COMPOSITIONS ANDMETHODS FOR TREATING INFLAMMATION CROSS REFERENCES TO RELATEDAPPLICATIONS This application is a continuation-in-part of co-pendingapplication U. S. Ser. No. 699,022 filed Jan. 19, 1968, now abandoned,which latter case is a continuation-in-part of U. S. Ser. No. 577,819filed Sept. 8, 1966, now abandoned, which latter case is itself acontinuation-in-part 420,823 filed Dec. 23, 1964, now abandoned.

BACKGROUND OF THE INVENTION 1. Field of Invention Generally, thisinvention relates to substituted S-(phenyl) benzoic acids, esters andnon-toxic pharmaceutically acceptable salts thereof for use in thetreatment of inflammatory type diseases. It is an object of thisinvention to prepare compounds having anti-inflammatory properties butnot having many of the side effects which are generally associated withsteroid type anti-inflammatory agents. Prior to this time, steroid typeanti-inflammatory agents such as CORTONE, HYDROCOR- TONE and DECADRONwere commonly used to relieve inflammation but as stated, thesecompounds exhibit many undesirable side effects.

2. Description of the Prior Art The closest prior art compounds whichcould be found are those shown and described in U. S. Pat. Nos.2,744,916 and 3,123,543. Neither of these patents disclose ananti-inflammatory use for the compounds. These references disclose 2-hydroxy-S-phenyl benzoic acid (S-phenyl salicylic acid) and variousester and amide derivatives thereof. Also the prior art discloses acetylsalicylic acid (aspirin). The compounds of the instant invention,however, are more potent than the prior art compounds at lower dosagesand exhibit fewer side effects than the prior art compounds. The priorart compounds disclosed in the two patent references are not substitutedwith halo or halo groups on the phenyl moiety attached to the 5-position of the benzoic acid.

SUMMARY OF THE INVENTION AND DESCRIPTION OF THE PREFERRED EMBODIMENTSThis invention relates to new biphenyl compounds, and to a method oftreating inflammation using these compounds and to processes forproducing the same. More specifically, this invention relates tosubstituted 5-(phenyl)benzoic acids, esters, amides, anhydrides andnon-toxic pharmaceutically acceptable salts thereof. Still morespecifically, this invention relates to compounds having the generalformula:

wherein X( 1-5) is halo, such as fluoro or chloro but especially fluoro;X being on one or more of the phenyl carbon atoms;

R l is selected from the group consisting of hydroxy, phenoxy,diloweralkylamino, (such as, dimethylamine), diloweralkylaminoloweralkoxy (such as diethylaminoethoxy);

R is selected from the group consisting of hydrogen and lower alkanoyl(such as acetyl, propionyl and butyryl);

R is selected from the group consisting of hydrogen and methyl. Alsoincluded in the compounds of this invention are the pharmaceuticallynon-toxic salts of the acids of the compounds of Formula I such as theammonium, alkali metal (such as sodium or potassium); alkaline earthmetals (such as calcium, barium or magnesium); amine; aluminum; iron;choline; glucosamine; S-methyl methonine salts, piperazine,diloweralkylamino lower alkanol, chloroquine and hydroxy of applicationU. S. Ser. No. l0

chloroquine; the anhydride of said acids, the mixed anhydrides of saidacids and 2-acetoxy benzoic acid.

' In the especially preferred aspects of this invention,

R is hydroxy,

R is hydrogen or acetyl,

R is hydrogen and X being on any position of the phenyl moiety when X isone fluoro group but particularly on the 4'-position and on any one orcombination of the other positions of the phenyl moiety when Xrepresents 2-5 fluoro groups.

Representative compounds of this invention are as follows:

2-hydroxy-5-(4'-fluorophenyl)benzoic acid;

2-acetoxy-5-(4"fluorophenyl)benzoic acid;

2-hydroxy-5-( 2fluorophenyl)benzoic acid;

2-hydroxy-5-( 3 '-fluorophenyl )benzoic acid;

2-hydroxy-S-pentafluorophenyl benzoic acid;2-hydroxy-3-methyl-5-(4'-fluorophenyl )benzoic acid;2-hydroxy-5-(4-chlorophenyl)benzoic acid;

B-diethylaminoethyl-5-( 4-fluorophenyl )salicylate;

aluminum-2-acetoxy-5-(4'-fluorophenyl)-benzoate salt;aluminum-2-hydroxy-5-( 4-fluorophenyl)-benzoate salt;choline-2-acetoxy-5-(4-fluorophenyl)-benzoate salt;choline-2-hydroxy-5-(4'-fluorophenyl)-benzoate salt;sodium-2-acetoxy-5-(4-fluorophenyl)-benzoate salt;sodium-2-hydroxy-5-(4-fluorophenyl)-benzoate salt; 2-hydroxy-5-(pentafluorophenyl )-benzoic acid; 2-acetoxy-5-(pentafluorophenyl)-benzoic acid;

,B-diethylaminoethyLZ-hydroxy-5-(4-fluorophenyl)- benzoate;

B-diethylaminoethyl-Z-acetoxy-S-(4'-fluorophenyl)- benzoate.

This invention also relates to a method of treating inflammation inpatients using a compound of Formula l, particularly an especiallypreferred compound as the active constituent.

We have found that the compounds of Formula I have antiinflammatoryactivity and are effective in the prevention and inhibition of edema andgranuloma tissue formation as shown by reduction of edema in the ratsfoot induced by the injection of an inflammatory (phlogistic) agent intothe rats foot.

The compounds of the instant invention can be used to treat inflammationby reducing inflammation and relieving pain in such diseases asrheumatoid arthritis, osteoarthritis, gout, infectious arthritis andrheumatic fever. Furthermore, the compounds of the instant inventionhave better potency at the same dosage levels than similar typecompounds known in the prior art and exhibit a lower incidence of sideeffects.

The compounds of Formula I also have anti-pyretic and analgesic activityand would be administered and used in the same manner and in the samedosage ranges as if they were being used to treat inflammation asdiscussed further on.

The especially preferred compounds of the instant invention exhibit inaddition to potent anti-inflammatory effects a smaller incidence ofvomiting (emesis effect) than do similar type compounds of the priorart, especially acetyl salicylic acid (aspirin) type compounds. Theespecially preferred compounds of the instant invention all have abetter therapeutic ratio than does aspirin.

The treatment of inflammation in accordance with the method of thepresent invention is accomplished by orally administering to patients acomposition of a compound of Formula I, particularly the especiallypreferred compounds in a non-toxic pharmaceutically acceptable carrier,preferably in tablet or capsule form.

The non-toxic pharmaceutical carrier may be for example, either a solidor a liquid. Exemplary of solid carriers are lactose, corn starch,gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba,sucrose, agar, pectin, cab-o-sil, and acacia. Exemplary of liquidcarriers are peanut oil, olive oil,

sesame oil and water. Similarly, the carrier or diluent may include atime delay material such as glyceryl monostearate or glyceryl distearatealone or with a wax.

Several phannaceutical forms of the therapeutically useful compositionscan be used. For example, if a solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelatin capsule, asyrup or a liquid supsension.

The active compounds of Formula I and of the compositions of thisinvention are present in an amount sufficient to treat inflammation,that is to reduce inflammation. Advantageously, the composition willcontain the active ingredient, namely, the compounds of Formula I in anamount of from about 1 mg. to 140 mg. per kg. body weight per day (50mg. to 10 g. per patient per day), preferably from about 2 mg. to 70 mg.per kg. body weight per day 100 mg. to 5 g. per patient per day).

The method of treatment of this invention comprises internallyadministering to a patient (animal or human), a compound of Formula I,particularly an especially preferred compound admixed with a non-toxicpharmaceutical carrier such as exemplified above. The compounds ofFormula I and particularly the especially preferred compounds will bepresent in an amount of from 1 mg. to I40 mg./kg. body weight per day,preferably from about 2 mg. to about 70 mg. per kilogram body weight perday and especially from 4 mg. to mg./kg. body weight per day. The mostrapid and elTective anti-inflammatory effect is obtained from oraladministration of a daily dosage of from about 4 to 10 mg./kg./day. Itshould be understood, however, that although preferred dosage ranges aregiven, the dose level for any particular patient depends upon theactivity of the specific compound employed. Also many other factors thatmodify the actions of drugs will be taken into account by those skilledin the art in the therapeutic use of medicinal agents, particularlythose of Formula I, for example, age, body weight, sex, time ofadministration, route of administration, rate of excretion, drugcombination, reaction sensitivities and severity of the particulardisease.

The test method by which anti-inflammatory activity is determined is bythe ability of the compounds of Formula I to inhibit the edema inducedby injection of an inflammatory phlogistic) agent into the tissue of thefoot of the rat. Groups of six male rats (Sprague Dawley strain, 150 ig.) each are given orally the compounds to be tested one hour before 0.1ml. of 1 percent suspension of carragenin is injected into the plantarsurface of the right hind paw. Immediately and again three hours later,the foot volume is measured by its displacement of mercury and recordedautomatically. The difference between the immersion and final volumes isa measurement of the edema produced. The compounds tested were suspendedor dissolved in 0.5 percent methocel whereas controls received only themethocel. A usual test of 30 mg./kg. and one repetition plus one dose of90 mg./kg. were usually given.

The above test method is known to correlate with anti-inflammatoryactivity in humans and is a standard test used to determineanti-inflammatory activity. This correlation is shown by compounds knownto be clinically active, including, INDOCIN, ASPIRIN, BUTAZOLIDIN,TANDEARIL, COR- TONE, HYDROCORTONE and DECADRON. The test results forthe compounds shown in Formula I above are compared with similar testsrun on the closest of the prior art compounds which applicants coulddetermine, namely, 5-phenyl salicylic acid and the correspondingderivatives thereof disclosed in Sayhun et al., U. S. Pat. No. 2,744,916and 3,123,543 and acetyl salicylic acid (aspirin). The results of thesetests are as follows:

Dose Edema Applicants Compounds mg/kg Inhibition2-hydroxy-S-(4'-fluorophenyl) 3.33 18 benzoic acid 10 47 30 73 90 772-acetoxy-5-(4'-fluorophcnyl) 3.33 25 benzoic acid 10 37 Average I0 55of 70 5 tests 2-hydroxy-5-( 2'-fluoropheny l0 3 3 benzoic acid 30 56 9069 2-hydroxy-5-(2',4'-difluoro- 3.33 24 phenyl)benzoic acid 10 51Average 30 66 of 90 77 2 tests 2-hydroxy-5-(3'-fluorophenyl) 10 28benzoic acid 30 52 2-hydroxy-5-pentafluoro- 1O 47 phenyl benzoic acid 3056 90 68 2-hydroxy-3-methyl-5-(4'- fluorophenyhbenzoic acid 30 4I2-hydroxy-5-( 4-chlorophenyl) IO 13} Average benzoic acid 30 27 of 2 52tests N ,N-dimethyI-2-hydroxy-5- (4-fluorophenyl)benzamide 30 23fl-cliethylaminoethyI-2-hydroxy- 10 l 9 5-(4-fluorophenyl)benzoate 30 35phenyI-2-hydroxy-5-(4'-fluoro- I O 29 phenyl)benzoate 30 54 Dose EdemaPrior Art Compounds mg/kg Inhibition S-phenyl salicylic acid or2-hydroxy-5-(phenyl 5O 42 Average benzoic acid I00 51 of tests 333 l0 930 21 90 79 N,N-dimethyl-5-phenyl 5O 7 Average salicylamide 100 17 of 3tests 200 27 phenyl-S-phenyl salicylate 50 11 Average I00 26 of 2 (051.8B-diethylaminoethyl-S- 50 7 Average phenyl salicylate HC] 100 29 of 2tests acetyl salicylic acid 3.33 16 Avg.

2 tests (aspirin) (2-acetoxybenzoic acid) 30 21 Avg.

5 tests 90 39 Avg.

4 tests 60 Avg.

3 tests 270 74 Avg.

3 tests In each instance above, the activity of the compounds shown inFormula I was greatly enchanced by the presence of a halo group,particularly the fluoro group in the prime phenyl moiety of thecompound. In one pair, namely 2-hydroxy-5- phenyl salicylic acid(2-hydroxy-5-phenyl benzoic acid) and 2-hydroxy-5-(4'-fluorophenyl)benzoic acid, a statistical anal-' ysis was made on the data on edemavolume obtained as previously shown. It was determined that2-hydroxy-5-(4'- flu0r0phenyl)benzoic acid is 4. I 5 times as potent as2-hydroxy-S-phenyl benzoic acid of the prior art. Statistical datashowed that if this test were repeated, the compound, 2-hydroxy-5-(4'-fluorophenyl)benzoic acid, of Formula I would be at least3.11 times as potent in reducing inflammation as the 2-hydroxy-5-pheny1benzoic acid of the prior art, but not 5.62 times as potent. Also in theabove comparisons and from the above data, 2-hydroxy-5-phenyl benzoicacid when given at a dose of 90 mg./kg. approximately matches the effectof 2- hydroxy-S-(4-fluorophenyl)benzoic acid at less than onethird thedoes. In other words, the addition of fluorine at least tripled thepotency in this particular compound. Generally, it can be seen that thecompounds of the instant invention are more potent at lower dosageranges than compounds of the prior art.

In addition to the above tests, the potency of three of applicantscompounds relative to the best prior art compound, namely, S-phenylsalicylic acid, was estimated recently in the rat foot-edema test aspart of a multiple assay. Three graded doses of each preparation wereadministered orally to individual groups of six rats. All rats weregiven an intraplantar injection of carrageenan (0.1 ml. of a 1 percentsuspension in is known, require the appropriate reactions to obtain thefuncthe right hind paw) approximately 1 hour after receivinG the tionalgroup, if needed, as well as the metal salts. However, all testpreparations. Three hours later. the volume of the edeof the compoundsmay be obtained by first preparing an matous foot was measured using amercury displacement aniline compound containing an X followed by aGomberg technique. This test method is similar to the one previously 5reaction with nitrobenzene or anisole or an R (methyl) subdescribed.stituted nitrobenzene or anisole, subsequently reacting either The assaywas replicated four times since one of the experithe nitro group or themethoxy group (from nitrobenzene or mental objectives a .w to study dayto day variability among anisole) of the biphenyl compound thus preparedso as to obrelative potency estimates. For 2-acetoxy5-(4'-flu0rophentainthe alkali salt starting material. For example, 2-fluoro-5- yl)benzoicacid, the four estimates of relative potency varied 10 nitroaniline maybe diazotized to the corresponding 2-fluorofrom 4.97 to 8.13, a ratio of1.6 for highest to lowest. 2- 5-nitrophenol and said nitrophenol reducedto obtain the aphydroxy-S-t 4'-fluorophenyl)benzoic acid varied from5.20 to propriate aniline compound needed for the Gomberg reac- 8.56, aratio of 1.6, as for 2-acetoXy-5-(4-flu0rophention. (When as in thiscited example, the benzene compound yUb zoic acid- However. these i notdiffer gnifi n y contains an alkoxy group the Gomberg reaction iscarried out from a ratio of 1.0, indicating that the estimates were wi hnitrobenzene), The nitrobi henyl compound thus obhomogeneous within thelimits of experimental error. On the r i d may b adil r du ed to theamino compound and other hand, Z-hydroxy-S-pentafluorophenyl benzoi acidsubsequently diazotized to the corresponding hydroxy comvaried from 3.05to 7.25, a ratio of 2.4. This indicated signifipound, Alt a i el whenthe aniline compound used in the cant heterogeneity among the estimatesat P 0- Gomberg reaction does not have an alkoxy substituent on it, it

Table 1 below shows average foot volume for each of the may b reacted ih a alk benz n rather than preparations. The estimates of relativepotency and 95 pernitrobenzene. Using this procedure, the alkoxybiphenyl com- Cent confidence mils (estimated using Dunnefl's I arepound obtained after the Gomberg reaction may, by one step, marized inTable 11, also included below. The combined estib v ned to thcorresponding hydroxy-biphenyl commate of relative (i.e., replications1-4) is also shown in this tao nd, for example by reaction withhydriodic acid.

ble. All replicates showed valid results (i.e., linearity andparallelism) except replicate 4, which showed a lack of parallellism atl 0.05v However, since this was not observed in any Although h abovereaction sequence can be u sed when, of the other replicates1 theapparent lack of parallelism was Is methyl, 1t 1s preferred to carry outthe following reaction ignored and average relative potenciescalculated. Since Sequence f methyl For examplc the methyl?- 1. wassmall (varying from 0035 to 0067 the data were hydroxy-5-(4-fluorophenyl)-benzoate ester compound is combined using the weightedprocedure Suggested by Bliss reduced to the corresponding alcohol. Thisalcohol compound (vitamin Methods n Academic Press Inc. Publishers, Newis then acylated, whereupon it is subsequently hydrogenated York, 1951,pp. 576-582). The replicate variance was added to the cofrespondmg'fluorp} enyl)'2'methylphenyl to the intrinsic variance of the assaysfor acetate. This compound 15 then saponified or hydroly zed totafluorophenyl benzoic acid. (g is defined in Finney, D. J. theconespondmg phenol compound wh'ch m tum car- Statistical Method inBiological Assay. p. 17, 28,34, 114 and 9 other pages. Hafar Publ. Co.,New York, 2nd Ed., 1964.) benzmc acld TABLE I AVERAGE FOOT VOLUMES I v Ip I of mm 40 In the Gomberg reaction mentioned above, a mixture of odisp lac em y isomers of the biphenyl compound is obtained; therefore,in order to obtain the desired 4-(substituted phenyl)-benzene Ffllilbiicompound in a pure form a chromatographic separation is Preparation Ilose 1 2 3 4 required. 2'hydr0Xy-5-(phrnylllmnzuir' acid 10 .55 .74 .60.68 The 4-(substituted phenyl)-phenol compounds obtained as describedabove may then be converted to the corresponding em 24 .36 .21: 26

alkah salt by any well-known means, for example, reaction2-acetoxy-5M'-fluoropl1rnyl) hvnzuir- 3. 3 42s .65 .52 53 i anappropriate k i metal i an inert Solver acid. 10 .36 .47 .3; .23

The acid corn unds of this invention ma be prepared 56 P Y I 1 .45 2 My5 (4 fiuomphenynbenm g in 33 from the previously prepared alkallphenolate or phenol com- 30 pound. The preparation of these acidcompounds are carried 2-hydr0Xy-5-pe11lufluorophenyl benzolc 3.3 38 .76.50 .53 out by using the well-known Kolbe-Schm1dt carbonauon acid. g8 g53 -5 procedure. In th1s carbonation step, the phenolate is reacted 55with carbon dioxide or the phenol is reacted with carbon diox- TABLE 112-acet0xy-5-(4-fluorophe11yl)benzoic acid... 4.97-(2,544.70)5.10-(3.l48.30) 5. 544110841141) 8.13(4.5214.G6) 5. 78-(4.52-7.38)2-hydroxy-s-(4'-nuo1-ophenyl)benzoic acid... 5. 20-(2.66-10.02)5.96-6.64-175) ass-(4.634585) 5.s1-(3.30-10.23) 6. 25(4.888.00)2-hydroxy-S-pentafluorophenyl benzoic acid"... 6.23-(3. 14-12. 361 3.05.(1.00-1.90) 7.25-(3.9713.23) .'l.98(2.206.90) 4.71-(2. 49-8, 89)

Potency and confidence limits of 2-acetoxy-5-(-l-i1u0rophenyl) henzoicacid, 2-hydroxy-fi'rl lluorophenyl)beuzoic acid, and2-hydroxy-5-pentnfluorophenyl benzoic acid; relative to2-hyd1-oxy-5-(pl1enyl)benzoic acid.

The compounds of this invention may be prepared either ide in thepresence of an alkali carbonate. The process may be from a biphenylphenol or from the following type starting shownasfollows:

. O-s) l u-s) i 0A R; R3

fl-fl g wherein: 1&1,

A'is an alkali metal ion; and X and R, are as previously defined. Q Q01!Some of these compounds are prepared from the individual phenyl moietiesof the above starting material by the wellknown Gomberg reaction.Others, where the biphenyl moiety (3) Equivalents:

As previously indicated. Reactions and Conditions Step 1.

Reaction with carbon dioxide at elevated temperatures (above 75 C.preferably above 100 C.) with or without a solvent preferably without asolvent (or if the solvent is used, any high-boiling inert solvent maybe used) until the reaction is substantially complete; and subsequentacidification of the reaction mixture.

Step 2.

Reaction with carbon dioxide in the presence of an alkali carbonate,such as potassium, sodium, and the like, especially potassium, atelevated temperatures (above 75 C. preferably above 100 C.) with orwithout a solvent preferably without a solvent (or if the solvent isused, any high boiling inert solvent may be used) until the reaction issubstantially complete; and subsequent acidification of the reactionmixture.

Reaction Steps (1) and (2) are the well-known Kolbe- Schmidt reaction.Since the reaction conditions are not critical, this inventioncontemplates not only the particular procedure shown but all othervariations of this carbonation step which are well-known in the art.

The compounds of this invention, wherein R, is a group such that anester is the final compound, (i.e., R, =phenoxy or diethylaminoethoxy),may be prepared by any esterification procedure, using an esterifyingagent containing the appropriate R, group. For example, the benzoic acidcompound of this invention may be reacted with the appropriatehydroxylic compound at elevated temperatures in the presence of a strongacid to form the desired R, compound. In the case of compounds where R,is phenyl, a mixture of the acid, phenol and phosphorous oxychloride isheated to produce the desired product. In the case wherein R, isdiethylaminoethoxy, the potassium salt of the acid is reacted withdiethylaminoethylchloride to produce the desired ester.

The compounds of this invention, wherein R, is a group such that anamide is the final compound (i.e., R, is dimethylamino), may be preparedby any suitable amidation reaction. For example, the benzoic acidcompound (preferably the methyl or ethyl ester) may be reacted with anamine compound, at any suitable temperature (room temperature toreflux).

The final compound, wherein R is lower alkanoyl (preferably acetyl), maybe prepared by any suitable alkanoylation reaction. For example, thecorresponding hydroxy benzoic acid, ester, or amide (preferably theester) may be reacted with a lower alkanoic acid anhydride (preferablyacetic anhydride) in the presence of a catalyst such as sulfuric acid,pyridine, p-toluenesulfonic acid, and the like (preferably pyridine), atany suitable temperature (room temperature to elevated temperatures)preferably at elevated temperatures to form the desired R compound.

The salts of the final acid compounds of this invention may be preparedby any of the well-knOwn methathesis procedures. For example, thebenzoic acid compound may be reacted with an inorganic base, such assodium hydroxide, potassium hydroxide, ammonium hydroxide, bariumhydroxide, and the like. The anhydrides of this invention may beprepared by any of the well-known procedures in the art.

The preparation of these compounds containing the R, and R groups otherthan hydrogen may be prepared in any order. The R, group could be placedon the molecule followed by addition of the R substituent or by firstobtaining the R compound followed by addition of the R, group. The orderof these reactions is not critical; they can be run in any desiredfashion.

The following examples are used by way of illustration:

EXAMPLE I 4-(4'Fluorophenyl)aniline A solution of 3 grams4-fluoro-4-nitrobiphenyl in 125 ml.

methanol is reduced by hydrogen at room temperature and 40 psi. pressureusing lOO mg. platinum oxide catalyst. After the required uptake ofhydrogen, the mixture is filtered, 50 ml. 2.5 N hydrochloric acid addedand the resulting solution is evaporated in vacuo. After washing theresidue with ether, it is dissolved in methanol, filtered and dilutedwith excess ether. The precipitate which is 4-(4'-fluorophenyl)anilinehydrochloride is filtered washed with ether and dried in vacuo at roomtemperature.

EXAMPLE 2 2', 3', 4, 5', 6"Pentafluoro-4-nitrobiphenyl A mixture of 7.5grams of pentafluoroaniline, 200 ml. of nitrobenzene, and 9.0 grams ofiso-amyl nitrite, is warmed on the steam bath until a vigorous reactionwith evolution of gas sets in. This evolution is allowed to proceedwithout heating until it has subsided, and the mixture is then heated onthe steam bath for an additional 3 hours. The excess of nitrobenzene isremoved in vacuo. The residue is purified for the desired isomer byelution from a silica gel column using petroleum-benzene to yield 2, 3',4', 5', 6-pentafluoro-4- nitrobiphenyl.

When 2-fluoroaniline is used in place of pentafluoroaniline in the aboveexample, there is obtained 2'-fluoro-4- nitrobiphenyl.

When Z-nitrotoluene is used in place of nitrobenzene in the aboveexample, there is obtained the corresponding 3-methyl biphenyls.

When 4-fluoroaniline and 2-methyl-nitrobenzene are used in the aboveexample in place of pentafluoroaniline and nitrobenzene, there isobtained 4'-fluor o-3-methyl-4- nitrobiphenyl.

EXAMPLE 3 4-(pentafluorophenyl)aniline A mixture of 5 grams of 2, 3, 4,5', 6'-pentafluoro-4- nitrobiphenyl in 250 ml. of ethanol is reduced byhydrogen at atmospheric pressure and at room temperature using 5 percentpalladium-on-charcoal (0.5 gram) catalyst. After the required uptake ofhydrogen, the mixture is filtered and the catalyst washed with freshethanol. The ethanol solution is then concentrated in vacuo, and theresidue recrystallized from aqueous ethanol to yield4-(pentafluorophenyl)-aniline.

When 2'-fluoro-4-nitrobiphenyl is used in place of 2, 3, 4', 5,6-pentafluoro-4-nitrobiphenyl in the above examples, there is obtained4-(4'-fluorophenyl)-aniline.

Similarly, when 4'-fluoro-3-methyl-4-nitrobiphenyl obtained from Example2 is used in place of 2', 3, 4', 5', 6'-pentafluoro-4-nitrobiphenyl inthe above example, there is obtained2-methyl-4-(4'-fluorophenyl)-aniline.

EXAMPLE 4 4-(3'-Chloro-4-fluorophenyl)-anisole A mixture of 8.0 grams of3-chloro-4-fluoroaniline, 200 ml. of anisole, and 9.0 grams ofiso-amyl-nitrite, is warmed on a steam bath until a vigorous reactionwith evolution of gas sets in. This evolution is allowed to proceedwithout heating until it has subsided, and the mixture is then heated onthe steam bath for an additional 3 hours. The excess anisole is removedin vacuo, and the residue is chromatographed on a silica gel columnusing petroleum-benzene as eluent to yield 4-(3-chloro-4'-fluorophenyl)-anisole.

When 2-chloro-4-fluoroaniline, 2,.4-difluoroaniline and 3- fluoroanilineare used in place of 3-chloro-4-fluoroaniline in the above example,there are obtained the corresponding 4-(2'-chloro-4'-fluorophenyl)-anisole, 4-( 2',4-difluorophenyl)- anisoleand 4-( 3-fluorophenyl)-anisole.

When Z-methylanisole is used in place of anisole in the above example,there is obtained the corresponding Z-methyl- 4-(substitutedphenyl)anisole.

EXAMPLE 5 4-( 3 -Chloro-4-fluorophenyl )-phenol To a solution of 2.1grams of 4-(3-chloro-4-fluorophenyl)-anisole in 50 ml. of boiling aceticacid is added 5 ml. of hydriodic acid and the boiling continued for 3hours. Water is added and the reaction mixture cooled and the4-(3-chloro- 4-fluorophenyl)-phenol crystallizes. Further purificationis then achieved by recrystallization of the solid from aqueous ethanolto yield 4-( 3 -chloro-4-fluorophenyl)-phenol.

When 4-(2'-chloro-4'-fluorophenyl)-anisole, 4-(2',4-difluorophenyl)-anisole and 4-(3'-fluorophenyl)-anisole obtained fromExample 4 are used in place of 4-(3-chloro-4- fluorophenyl)-anisole inthe above example, there are obtained the corresponding4-(2-chloro-4'-fluorophenyl)- phenol, 4( 2',4difluorophenyl)-phenol and4-( 3 '-fluorophenyl)-phenol.

When the 2- or 3-alkylphenyl-anisole compounds obtained from Example 4above are used in place of 4-(3'-chlo1"o-4- fluorophenyl)-anisole in theabove example, there is obtained the corresponding 4-(substitutedphenyl)-2-methyl phenol compound.

EXAMPLE 6 4-(4'-Fluorophenyl)-phenol A solution of 32.66 grams of4-(4-fluorophenyl)-aniline in 120 ml. of glacial acetic acid is cooledto l12 C. To this solution is added slowly a solution of 12.25 grams ofsodium nitrite in 120 ml. of water with stirring and continued cooling.Five minutes after this addition, the suspension of the diazoniumacetate is added slowly to a boiling solution of 100 ml. of concentratedsulfuric acid and 200 ml. of water. After the final addition of thediazonium salt, the suspension is boiled for an additional minutes andthen allowed to cool to room temperature. The reaction mixture is thenfiltered and the cake dried in vacuo to yield 4-(4-fluorophenyl)phenol,(m.p. 15216l C., 24.07 grams).

When 4-(2'-fluorophenyl)-aniline, 4-(penta-fluorophenyl)- anilineobtained from Example 3 are used in place of 4-(4'-fluorophenyl)-aniline in the above example, there are obtained thecorresponding 4-(2'-fiuorophenyl)-phenol and 4-(pentafluorophenyl)-phenol.

When the methyl aniline compound obtained from Example 3 is used inplace of 4-(4'-fluorophenyl)-aniline in the above example, there isobtained the corresponding 2-methyl phenol compound.

Similarly, when 2-methyl-4-(4'-fluorophenyl)-aniline obtained fromExample 3 is used in place of 4-(4-fluorophenyl)- aniline in the aboveexample, there is obtained 2-methyl-4-(4 -fluorophenyl)-phenol.

EXAMPLE 7 2-Hydroxy-5-(4'-fluorophenyl)-benzoic acid A mixture of 10grams of 4-(4'-fluorophenyl)-phenol and 27.2 grams of potassiumcarbonate is exposed to carbon dioxide at l,300 psi. and 175 C. The darkmass obtained from this carbonation is then dissolved in 300 ml. ofwater and 200 ml. of methylene chloride and the two layers separated.The water layer is then extracted with 100 ml. of methylene chloride andthen acidified with 2.5 N hydrochloric acid. This mixture is thenfiltered and the cake dried in vacuo to yield 5 .32 grams of the crudeproduct. The crude product is then recrystallized from benzene-methanolto yield 2.7 grams of material (m.p. 200-204 C.). An additionalcrystallization of this semi-pure material from benzenemethanol yieldsanalytically pure 2-hydroxy-5-(4'-fluorophenyl)-benzoic acid (m.p.l99-203 C.

When 4-(3'-chloro-4'-fluorophenyl)-phenol, 4-(2-chloro-4-fluorophenyl)-phenol, 4-(2,4'-difluorophenyl)-phenol and4-(3-fluorophenyl)-phenol obtained from Example 5 and 4'-(2'-fluorophenyl)phenol and 4-(pentafluorophenyl)-phenol obtained fromExample 6 are used in place of 4-(4- fluorophenyl)-phenol in the aboveexample, there are obtained the corresponding 2-hydroxy-5-(3-chloro-4"l'luorophenyl)benzoic acid, 2-hydroxy-5-(2-chloro-4- 10fluorophenyl)-benzoic acid, 2-hydroxy-5-(2',4'-difluorophenyl)-benzoicacid (m.p. 2l0-21l C.), 2-hydroxy-5-(3'- fluorophenyl)-benzoic acid(m.p. 196-l97 C.), 2-hydroxy-5- (2-fluorophenyl)-benzoic acid (m.p.20l203 C.) and 2- hydroxy 5-(pentafluorophenyl)-benzoic acid (m.p.24l-243 C.).

When the 4-(substituted phenyl)-2-methyl phenol compounds of Examples 5or 6 are used in place of 4-(4'- fluorophenyl)phenol in the above, thereare obtained 2- hydroxy-3 -methyl-5-( 3 -chloro-4'-fluorophenyl)-benzoic acid and 2-hydroxy-4-methyl-5-(2-chloro-4-fluorophenyl)-benzoic acid, respectively.

Similarly, when 2-methyl-4-(4-fluorophenyl)-phenol obtained from Example6 is used in place of 4-(4'-fluorophenyl)- phenol in the above example,there is obtained 2-hydroxy-4-(4 -fluorophenyl)-3-methyl-benzoic acid.

EXAMPLE 8 Sodium-2-hydroxy-5-(4-fluorophenyl)-benzoate A mixture of 0.1mole of 2-hydroxy-5-(4'-fluorophenyl)- benzoic acid and 0.1 mole ofsodium hydroxide in 100 ml. of water is stirred at room temperature forone-half hour. The reaction mixture is then concentrated in vacuo toyield sodium-2-hydroxy-5-(4-fluorophenyl)-benzoate.

When the benzoic acid compounds obtained from Example 7 are used inplace of the 2-hydroxy-5-(4'-fluorophenyl)- benzoic acid in the aboveexample, there are obtained the corresponding sodium salts.

Similarly, when choline, glucosamine, S-methylmethionine, potassiumhydroxide, ammonium hydroxide, barium hydroxide, calcium hydroxide,piperazine, chloroquine, hydroxychloroquine, dimethylaminoethanol, andmagnesium hydroxide, are used in place of sodium hydroxide in the aboveexample, there are obtained the corresponding choline, glucosamine,S-methyl-methionine, potassium, ammonium, barium, calcium, piperazine,chloroquine, hydroxychloro-quine, dimethylaminoethanol and magnesiumsalts, respectively.

EXAMPLE 9 A solution of 5.0 grams of 2-hydroxy-5-(4-fluorophenyl)-benzoic acid in 20 ml. of methanol and 2 ml. of concentrated sulfuricacid is heated at reflux for 5 hours. The mixture is then cooled andpartitioned between (751150 ml.) water and ethyl acetate and the organiclayer washed with dilute sodium bicarbonate solution. The organic layeris then dried over magnesium sulfate and concentrated in vacuo to yield5.3 grams (as an oil) of methyl-2-hydroxy-5-(4'-fluorophenyl)- benzoate.

When the benzoic acid compounds obtained from Example 7 are used inplace of 2-hydroxy-5-(4-fluorophenyl)-benzoic acid in the above example,there are obtained the corresponding methyl esters.

Similarly, when ethanol and n-butanol are used in place of methanol inthe above example, there are obtained the corresponding ethyl andn-butyl esters.

B. Phenyl-2-hydroxy-5-( 4-fluorophenyl)-benzoate A mixture of 6.4 gramsof 2-hydroxy-5-(4'-fluorophenyl)benzoic acid, 2.8 grams of phenol and1.7 grams of phosphorous oxychloride is heated at 114 C. until no morehydrogen chloride is evolved. The reaction mixture is cooled to roomtemperature and filtered. The resulting solid material is digested indilute sodium carbonate solution, filtered, washed with water, dried andrecrystallized from isopropyl alcohol to yield 4.0 grams of phenyl2-hydroxy-5-(4'- fluorophenyl)benzoate, m.p. 8 1 C.

Following the above procedure but using an equivalent amount of2-acetoxy-5-(4'-fluorophenyl)benzoic acid in place of2-hydroxy-5-(4'-fluorophenyl)benzoic acid, there is obtained phenyl2-acetoxy-5-(4-fluorophenyl) benzoate.

B-Diethylaminoethyl-2-hydroxy-5-(4'-fiuorophenyl)- benzoatehydrochloride A mixture of 4.0 grams (0.0175 mole) of 2-hydroxy-5-(4'-fluorophenyl)benzoic acid, 2.4 grams of potassium carbonate in 50 ml. ofisopropanol is refluxed for /& hr. 3.0 Grams (0.0175 m.) ofB-diethylaminoethylchloride.l-lcl. is added and the mixture refluxedwith stirring for hours. The reaction mixture is then distributedbetween water and ethyl ether. The ether layer is then washed withwater, dried and evaporated to a small volume. Dry hydrogen chloride gasis then passed into the ether solution and the resulting precipitate isfiltered and recrystallized from acetone/ethyl ether to yield B-diethylaminoethyl-2-hydroxy-5-(4-fluorophenyl)-benzoate hydrochloride.

EXAMPLE 10 N,N-Dimethyl-2-hydroxy-5-(4-fluorophenyl)-benzamide A mixtureof 5.3 grams of methyl-2-hydroxy-5-(4'- fluorophenyl)-benzoate and ml.of dimethylamine is reacted in a bomb at 100 C. for 4 hours. Aftercooling, the bomb is opened and the excess dimethylamine removed. Theresidue is then recrystallized from benzene to yield N,N-dimethyl-2-hydroxy-5-(4'-fluorophenyl)-benzamide which has a meltingpoint of 166 1 68 C.

When the benzoic acid methyl esters obtained from Example 9 are used inplace of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate in the aboveexample, there are obtained the corresponding N,N-dimethyl-benzamidecompounds.

EXAMPLE 1 l 2-Acetoxy-5-(4-fluorophenyl)-benzoic acid A solution of 3.0grams of 2-hydroxy-5-(4-fluorophenyl)- henzoic acid in 12 ml. ofpyridine and 8 ml. of acetic anhydride is heated on a steam bath for 20minutes. The mixture is then poured onto ice and the product extractedwith methylene chloride. The methylene chloride solution is dried andthen evaporated. The residue is recrystallized from benzene to yield2-acetoxy-5-(4'-fluorophenyl)-benzoic acid (m.p. 134l37 C.).

When the 2-hydroxy-benzoic acid compounds obtained from Example 7 areused in place of 2-hydroxy-5-(4- fluorophenyl)henzoic acid in the aboveexample, there are obtained the corresponding 2-acetoxy-benzoic acidcompounds.

Similarly, when propionic acid anhydride is used in place of aceticanhydride, the corresponding 2-propionoxy compound is obtained.

EXAMPLE 12 Anhydride of 2-acetoxy-4-(4'-flu0rophenyl)-benzoic acid Asolution of 0.01 mole of 2-acetoxy-4-(4'-fluorophenyl)- benzoic acid and0.01 mole of thionyl chloride in 30 ml. ofdry benzene is warmed untilthe formation of the substituted benzoyl chloride is complete. Theresulting solution is concentrated to one-half volume in vacuo and isadded to a solution of 0.01 mole of 2-acetoxy-4-(4-fluorophenyl)-benzoicacid and 0.01 mole of pyridine in 30 ml. of benzene. The mixture isstirred at room temperature overnight, filtered, and the filtrate washedwith cold dilute sodium bicarbonate solution. After drying and removalof benzene, the product is recrystallized from benzene-hexane.

Alternatively, the anhydride may be formed by reacting for 5 hours atroom temperature 0.02 mole of 2-acetoxy-4-(4'- fluorophenyl )-benzoicacid and 0.01 mole of dicyclohexylcarbodiimide in 20 parts oftetrahydrofuran, followed by filtration and concentration of thefiltrate to yield the anhydride.

When a solution of 2-acetoxy benzoic acid in pyridine is used in placeof the 2-acetoxy-4-(4-fluorophenyl)-benzoic acid pyridine solution inthe above example, there is obtained the mixed anhydride of2-acetoxy-4-(4-fluorophenyl)-benzoic acid and 2-acetoxy benzoic acid.

EXAMPLE l3 5-(4'-Fluorophenyl)-2-hydroxy-3-methyl-benzoic acid A.4-(4-Fluorophenyl)-2-hydroxymethyl-phenol A solution of 5.0 g. ofmethyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate in 25 ml. of ether isadded to a stirred suspension of 1.28 g. of lithium aluminum hydride inml. of ether at a rate sufficient to maintain gentle reflux. Heating atreflux temperature is continued for 0.5 hour after the addition. Theexcess hydride is decomposed with ethyl acetate, and sufficient dilutehydrochloric acid is added to make separation of the ether layerpossible. The ether phase is washed with water, dried over magnesiumsulfate, and concentrated to dryness. Trituration with hexane yielded3.93 g. of 4-(4-fluorophenyl)-2-hydroxymethylphenol, m.p. l50-157 C.Recrystallization from aqueous ethanol furnished pure material, m.p. 155-- 1 5 7 C.

B. 4-(4'-Fluorophenyl)-2-acetoxymethylphenyl acetate A mixture of 3.0 g.of 4-(4-fluorophenyl)-2-hydroxymethyl-phenol, 10 ml. of aceticanhydride, and 6 ml. of pyridine is heated on the steam bath for 1 hour.The reaction mixture is poured into ice water, stirred for 0.5 hour, andthe product extracted into ether. After drying with magnesium sulfateand treating with activated charcoal,4-(4-fluorophenyl)-acetoxymethylphenyl acetate is obtained as an oil.The yield is 3.95 g.

C. 4-(4-Fluorophenyl)-2-methylphenyl acetate A solution of 3.9 g. of4-(4-fluorophenyl)-2-acetoxymethylphenyl acetate in 30 ml. of glacialacetic acid is hydrogenated at 40 p.s.i. and 70 C. until the uptake ofhydrogen is one equivalent. The catalyst and solvent are removed, theproduct is taken up in ether, washed with dilute sodium bicarbonatesolution, dried, and the solution concentrated to dryness. The crudeyield is 2.95 g. Chromatography of 2.6 g. of the crude product on 1 10g. of silica gel furnishes 2.1 g. of pure4-(4'-fluorophenyl)-2-methylphenyl acetate, eluted with benzene, m.p.7173 C.

D. 4-(4'-Fluorophenyl)-2-methyl-phenol A mixture of 2.01 g. of4-(4'-fluorophenyl)-2-methylphenyl acetate, 10 ml. of ethanol, and 10ml. of 1.25 N sodium hydroxide is heated at reflux for 20 minutes. Thereaction mixture is concentrated to dryness in vacuo, and the residueredissolved in water. After acidification and extraction of the productwith ether, 1.6 g. of 4-(4'-fluorophenyl)-2-methylphenol is obtained,m.p. -13lC.

E. 5-(4'-Fluoropheny1)-2-hydroxy-3-methyl-benzoic acid A mixture of 1.5g. of 4-(4'-fluorophenyl)-2-methyl-phenol and 6 g. of anhydrouspotassium carbonate is heated in a bomb at 175 C. and 850 p.s.i. carbondioxide pressure for 16 hours. The reaction mixture is suspended in hotwater, acidified, and the cooled mixture extracted with ethyl acetate.The ethyl acetate was extracted repeatedly with portions of 1 percentsolution of sodium bicarbonate. The pooled bicarbonate extracts areacidified, and the product extracted into ether. After treatment withmagnesium sulfate and activated charcoal, the ether solution wasconcentrated to a small volume. The addition of hexane cause thecrystallization of 0.71 g. of5-(4'-fluorophenyl)-2-hydroxy-3-methyl-benzoic acid, m.p. 211-213 C.(sublimes).

When the 3-unsubstituted ester compounds of Example 9 are used in placeof methyl-2-hydroxy-5-(4'-fluorophenyl)- benzoate in the above example,there are obtained the corresponding 3-methyl benzoic acid compounds.

EXAMPLE 14 A dry filled capsule was prepared from the followingcomponents:

acid 300 mg. corn starch mg. Cab o sil 5 mg. Sterotex 15 mg.

A dry filled capsule can be prepared by using the following compounds asactive ingredients instead of 2-acetoxy-5-(4- fluorophenyl )-benzoicacid:

2-hydroxy-5-(4'-fluorophenyl)-benzoic acid;

13 2-acetoxy-5-(2',4'-difluorophenyl)-benzoic acid;2-hydroxy-3-methyl-5-(4'-fluorophenyl)-benzoic acid;phenyl-5-(4'-fluorophenyl )-2-hydroxy benzoate; 2-hydroxy-5-(3-fluorophenyl)-benzoic acid; or any other preferred compounds as shownin the specificaam.

If capsules of lower potency are to be made, the capsule size could bereduced or the quantity of corn starch could be increased.

EXAMPLE l5 Compressed tablets were prepared with the followingcomponents:

2-acetoxy-5 (4'-fluorophcnyl)-bcnzoic acid 300 mg. cornstarch 30 mg.polyvinylpyrrolidone l mg. magnesium stearate 3 mg.

t 3 Q u-s) Ill 3 wherein X is halogen;

R is hydroxy;

R is hydrogen or lower alkanoyl;

R is hydrogen or methyl; or a pharrnaceutically non-toxic salt of theacid,

2. A method of claim 1 wherein the compound to be administered is2-acetoxy3-methyl-5-(4'-fluorophenyl) benzoic acid.

3. A method of treating inflammation which comprises orallyadministering to a patient daily doses of from about 2 mg. to 70 mg./kg.body weight per day of a compound of the formula:

wherein R is hydrogen or lower alkanoyl or a pharmaceutically non-toxicsalt of the acid.

4. A method of claim 3 wherein the compound to be administered is2-hydroxy-5-(pentafluorophenyl) benzoic acid.

5. A method of claim 3 wherein the compound to be administered is2-hydroxy-5-(2'-fluorophenyl) benzoic acid.

6. A method of claim 3 wherein the compound to be ad ministered is2-hydroxy-5-(3'-fluorophenyl) benzoic acid.

7. A method of claim 3 wherein the compound to be administered is2-hydroxy-5-(2,4-difluorophenyl) benzoic acid.

8. A method of treating inflammation which comprises orallyadministering to a patient daily doses of from about 2 mg. to 70 mg./kg.body weight per day of a compound of the formula:

POOH

wherein R is hydrogen or lower alkanoyl or a pharmaceutically non-toxicsalt thereof.

9. A method of claim 8 wherein the compound to be administered is2-hydroxy-5-( 4'-fluorophenyl) benzoic acid.

10. A method of claim 8 wherein the compound to be administered is2-acetoxy-5-( 4-fluorophenyl) benzoic acid.

11. A method of claim 8 wherein the compound to be ad ministered is thecholine salt of 2-hydroxy-5-(4-fluorophenyl )benzoic acid.

12 A pharmaceutical anti-inflammatory composition consisting of aneffective amount of at least one member selected from the groupconsisting of the compounds of the formula:

COOH

wherein R is hydrogen or lower alkanoyl and a pharmaceutically non-toxicsalt thereof as an active ingredient together with a pharmaceuticallyacceptable carrier.

15. A composition as in claim 14 wherein the active ingredient is2-hydroxy-5-( pentafluorophenyl) benzoic acid.

16. A composition as in claim 14 wherein the active ingredient is2-hydroxy5-(2'-fluorophenyl) benzoic acid.

17. A composition as in claim 14 wherein the active ingredient is2-hydroxy-5-(3'-fluorophenyl) benzoic acid.

18. A composition as in claim 14 wherein the active ingredient is2-hydroxy-5-(2',4'-difluorophenyl) benzoic acid.

19. A pharmaceutical antiinflammatory composition consisting of aneffective amount of at least one member selected from the groupconsisting of the compounds of the formula:

wherein R is hydrogen or acetyl or a pharmaceutically nontoxic saltthereof, as an active ingredient, together with a pharmaceuticallyacceptable carrier.

20. A composition as in claim 19 wherein the active in- 22 A compositionas i l i 19 h i h active i grediemis y yp y acki gredient is the cholinesalt of 2-hydroxy-5-(4'-fluorophen- 21. A composition as in claim 19wherein the active inynbenzoic i grcdient is2-acetoxy-5-(4'-fluorophenyl) benzoic acid. I

2. A method of claim 1 wherein the compound to be administered is2-acetoxy-3-methyl-5-(4''-fluorophenyl) benzoic acid.
 3. A method oftreating inflammation which comprises orally administering to a patientdaily doses of from about 2 mg. to 70 mg./kg. body weight per day of acompound of the formula: wherein R2 is hydrogen or lower alkanoyl or apharmaceutically non-toxic salt of the acid.
 4. A method of claim 3wherein the compound to be administered is2-hydroxy-5-(pentafluorophenyl) benzoic acid.
 5. A method of claim 3wherein the compound to be administered is2-hydroxy-5-(2''-fluorophenyl) benzoic acid.
 6. A method of claim 3wherein the compound to be administered is2-hydroxy-5-(3''-fluorophenyl) benzoic acid.
 7. A method of claim 3wherein the compound to be administered is2-hydroxy-5-(2'',4''-difluorophenyl) benzoic acid.
 8. A method oftreating inflammation which comprises orally administering to a patientdaily doses of from about 2 mg. to 70 mg./kg. body weight per day of acompound of the formula: wherein R2 is hydrogen or lower alkanoyl or apharmaceutically non-toxic salt thereof.
 9. A method of claim 8 whereinthe compound to be administered is 2-hydroxy-5-(4''-fluorophenyl)benzoic acid.
 10. A method of claim 8 wherein the compound to beadministered is 2-acetoxy-5-(4''-fluorophenyl) benzoic acid.
 11. Amethod of claim 8 wherein the compound to be administered is the cholinesalt of 2-hydroxy-5-(4''-fluorophenyl)benzoic acid.
 12. A pharmaceuticalanti-inflammatory composition consisting of an effective amount of atleast one member selected from the group consisting of the compounds ofthe formula:
 13. A composition as in claim 12 wherein the activeingredient is 2-acetoxy-3-methyl-5-(4''-fluorophenyl)benzoic acid.
 14. Apharmaceutical antiinflammatory composition consisting of an effectiveamount of at least one member selected from the group consisting of thecompounds of the formula: wherein R2 is hydrogen or lower alkanoyl and apharmaceutically non-toxic salt thereof as an active ingredient togetherwith a pharmaceutically acceptable carrier.
 15. A composition as inclaim 14 wherein the active ingredient is2-hydroxy-5-(pentafluorophenyl) benzoic acid.
 16. A composition as inclaim 14 wherein the active ingredient is 2-hydroxy-5-(2''-fluorophenyl)benzoic acid.
 17. A composition as in claim 14 wherein the activeingredient is 2-hydroxy-5-(3''-fluorophenyl) benzoic acid.
 18. Acomposition as in claim 14 wherein the active ingredient is2-hydroxy-5-(2'',4''-difluorophenyl) benzoic acid.
 19. A pharmaceuticalantiinflammatory composition consisting of an effective amount of atleast one member selected from the group consisting of the compounds ofthe formula: wherein R2 is hydrogen or acetyl or a pharmaceuticallynon-toxic salt thereof, as an active ingredient, together with apharmaceutically acceptable carrier.
 20. A composition as in claim 19wherein the active ingredient is 2-hydroxy-5-(4''-fluorophenyl) benzoicacid.
 21. A composition as in claim 19 wherein the active ingredient is2-acetoxy-5-(4''-fluorophenyl) benzoic acid.
 22. A composition as inclaim 19 wherein the active ingredient is the choline salt of2-hydroxy-5-(4''-fluorophenyl)benzoic acid.